Lung Entrapment Secondary to Loculated Rheumatoid Effusions Treated With Alteplase and Dornase

Rheumatoid arthritis is a multisystemic inflammatory disease that can involve the respiratory system, including the pleural space. Most rheumatoid pleural effusions (PE) are incidentally found and do not require any treatment. Very rarely, however, they can become symptomatic and loculated, leading to lung entrapment or trapped lung. Surgical decortication remains the mainstay of management in such circumstances, although recent studies showed comparable efficacy of intrapleural fibrinolytics (alteplase and dornase alfa) in non-rheumatoid complicated effusions. We present a case of rheumatoid PE leading to lung entrapment successfully treated with intrapleural fibrinolytics without complications and good clinical status at six-month follow-up.


Introduction
Rheumatoid arthritis (RA) is a multisystemic inflammatory disease that primarily affects joints but can present with extra-articular pulmonary manifestations, including interstitial lung diseases, small and large airway diseases, lung nodules, and pleural effusions (PE) [1].Asymptomatic PE in RA are common, but they can be symptomatic in 3-5% of the cases.They tend to be exudative and are associated with high lactate dehydrogenase (LDH), high RA factor titers, low pH, and low glucose, and diagnosis generally requires ruling out other causes of PE, including tuberculosis and malignancy [2].Asymptomatic RA-associated PE (RPE) can be managed with clinical surveillance, as most effusions spontaneously resolve over time.In a minority of cases, systemic or intrapleural steroids are used to treat underlying inflammation, which usually results in clinical recovery [3].Very rarely, RPE can loculate and compromise respiration via restrictive physiology that has traditionally been managed with surgical decortication in symptomatic patients [2,4].Intrapleural fibrinolytics (alteplase and dornase alfa) have been established as a less invasive alternative to decortication surgery in patients with complicated effusions and have been shown to have comparable efficacy [5].However, its role in noninfectious loculated PE remains largely unexplored.
Herein, we present a case of a female with a history of RA who presented with subacute dyspnea and hypoxemia in the setting of loculated bilateral PE with lung entrapment secondary to rheumatoid pleurisy.She was treated with intrapleural fibrinolytics through a small-bore pigtail chest tube, which resulted in significant clinical and radiographic improvement.
This case report was presented as an abstract presentation at the American Thoracic Society (ATS) International Conference 2024, San Diego [6].

Case Presentation
A 63-year-old Caucasian female was referred to the emergency department (ED) by her primary care physician due to a one-month history of progressively worsening shortness of breath, fatigue, and gradually enlarging PE on outpatient serial chest X-rays.Additional symptoms included a recent recurrence of chronic joint pains and subjective fevers in the setting of a known diagnosis of RA for 24 years for which she was not taking any medications.She was otherwise vitally stable except for mild tachypnea and hypertension, and she required 2 liters of supplemental oxygen to maintain saturations >90%.Pertinent laboratory findings and arterial blood gas on 2 liters of supplemental oxygen are mentioned in Table 1.

Lab value
Reference range  The chest X-ray was concerning for bilaterally loculated (right greater than left) effusions that were confirmed on a CT scan of the chest (Figure 1).A transthoracic echo showed normal heart function.The patient was monitored for two days while an acute bacterial infection was ruled out, and she continued to be symptomatic and hypoxemic.In the setting of a high inflammatory state as reflected by a high serum C-reactive protein of 25 milligrams/deciliters and an erythrocyte sedimentation rate of 130 mm/hour, RA factor 1: 1024 units, anti-cyclic citrullinated peptide: 215 units, active arthritis symptoms, typical pleural fluid analysis without atypical cells x 2, negative QuantiFERON and AFB PCR, and medication noncompliance, this was thought to be RPE.Treatment options were discussed with a multidisciplinary team and the patient, and the decision was to place a small bore (14 French Wayne Pigtail catheter) in the chest tube for treatment with alteplase and dornase.
Two days later, at the time of chest tube placement, repeat thoracentesis showed worsening chemistry findings, including lower pH and glucose, higher LDH, a high pleural RA factor, and very high white blood cell counts with neutrophil predominance.AFB and fungal cultures (followed up for eight weeks) remained negative, and cytology was unremarkable.Further details are shown in Table 2 as thoracentesis 2. Despite empyematous-appearing pleural fluid findings, antibiotics were held as the patient did not show any clinical symptoms or laboratory findings of infection.The patient was treated with intrapleural administration of 10 mg of alteplase mixed with normal saline and 5 mg of dornase alfa mixed with water every 12 hours for three days.Treatment with fibrinolytics resulted in significant drainage of serosanguineous fluid over the next three days, resulting in dramatic symptomatic and radiographic improvement.The patient was discharged on low-dose prednisone.At a six-month follow-up at the rheumatology office, she was asymptomatic from a respiratory standpoint.

Discussion
Rheumatoid pleurisy can manifest with a broad spectrum of pleural pathologies.Typically, it presents with asymptomatic, small exudative effusions that often do not necessitate treatment.However, in rare instances, it may lead to complicated effusions such as large exudative sterile empyematous rheumatoid effusions, cholesterol (chyliform) effusions, empyema, hydropneumothorax, or pyopneumothorax, which may require pharmacological or invasive interventions [2,7].
Diagnosis generally requires pleural fluid analysis showing low glucose, low pH, high LDH, and high WBC count.Neutrophilic predominance typically occurs initially, followed by lymphocytic predominance [3].Interestingly, our patient initially exhibited lymphocytic predominance, followed by neutrophilic predominance upon repeat thoracentesis on the same side.This unusual trend could be attributed to fluid collection from different pockets due to loculations or the newer effusion resulting from ongoing inflammation, as reflected by systemic symptoms and elevated inflammatory markers.The possibility of a new pleural infection after previous thoracentesis or the risk of spontaneous infection in RPE was also considered but was unlikely.There was no fever or leukocytosis, and pleural fluid gram stains and cultures were negative, and the patient clinically improved without antibiotics.It is important to rule out malignancy and tuberculosis, as they may have similar features in pleural fluid analysis.If the diagnosis remains unclear, a thoracoscopic pleural biopsy may be warranted that may show the replacement of normal parietal mesothelial cells with inflammatory cells, tadpole cells, and multinucleated giant cells [8].We made the diagnosis based on classic pleural fluid chemistry, a very high RA titer in the pleural fluid, multiple negative cytology, and negative cultures and stains for AFB and fungi.
Recommendations for RPE treatment are mostly based on case reports and series.In many cases, RPE resolves spontaneously or requires only intermittent therapeutic thoracentesis for symptom relief [9,10].Nonetheless, some studies advocate for aggressive treatment approaches including systemic steroids, intrapleural steroids, or other immunosuppressives due to the potential progression of RPE leading to pleural thickening, lung entrapment, trapped lung, or fibrothorax, which may necessitate surgical interventions including decortication and/or pleurectomy [2,4,11,12].The use of less invasive interventions such as intrapleural fibrinolytics has been increasing in loculated parapneumonic effusions and empyema over the past decade, and recent studies showed their comparable efficacy and better quality of life index compared to surgery [5,13,14].However, data on treating severely loculated RPE with intrapleural fibrinolytics is very scarce, and to the best of our knowledge, there is only one abstract published regarding the management of loculated RPE with fibrinolytics [15].
Treatment decisions for our patients were made collaboratively, considering all potential risks and benefits.
The patient was symptomatic and had entrapment of the lungs, as reflected by severe pain and nonexpansion of the lungs upon therapeutic thoracentesis, which warranted further interventions to resolve the loculations.She was at high risk of intraoperative and postoperative complications, including delayed recovery, due to a history of coronary artery disease, low body mass index, and low albumin.She expressed reluctance to undergo surgery and showed a willingness to pursue fibrinolytics with a small-sized chest tube.Overall, the patient tolerated the procedure very well and was able to finish a three-day course with desired outcomes without significant pain.

Conclusions
This case highlights the potential utilization of intrapleural fibrinolytics through a small-bore chest tube for loculated RPE to resolve lung entrapment, which has not been reported much in medical literature before.Intrapleural fibrinolytics in our patient were well tolerated without any significant complications and resulted in significant clinical and radiographic improvement.Further studies comparing the safety and efficacy of intrapleural fibrinolytics and surgery in RPE patients would be warranted.

FIGURE 1 :
FIGURE 1: Axial view of CT scan chest showing large right-sided loculated effusion and medium to large left-sided effusion CT: computed tomography

FIGURE 2 :
FIGURE 2: Right-sided lung US showing loculated effusions and multiple septations US: ultrasound

FIGURE 3 :
FIGURE 3: Left-sided lung US showing a fibrin thread (loculations) attached to the diaphragm US: ultrasound